OCT3 activity inhibitor containing imidazopyridine derivative as active component, and OCT3 detection agent

ABSTRACT

To provide an OCT3 activity inhibitor having a different basic skeleton than that of conventional OCT3 activity inhibitors. This inhibitor of organic cation transporter 3 (OCT3) contains, as an active component, an imidazo[1,2-a]pyridine derivative, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

TECHNICAL FIELD

The present invention relates to an organic cation transporter 3 (OCT3)activity inhibitor containing an imidazopyridine derivative as an activecomponent, and an OCT3 detection agent.

BACKGROUND ART

Various pharmaceutical agents are used in a drug therapy. Some of theseagents become positive ions (cations) under biological conditions.Recently, a study of a transporter (transport protein), which exists ina cell membrane and contributes to migration of a pharmaceutical agentto a tissue, absorption thereof, renal excretion thereof and biliaryexcretion thereof by transporting the pharmaceutical agent actively, hasbeen significantly advanced. Among the transporters, an organic cationtransporter (OCT) is important to transport a cationic pharmaceuticalagent.

Recent studies have revealed that an OCT3 exists not only in theplacenta, but also in the kidneys, the small intestine, the lungs, theheart, and the brain.

A nucleoside derivative, a quinoline derivative, and a compound having atricyclic structure have been reported as OCT3 activity inhibitors.However, it is difficult to use these compounds as drugs because of sideeffects etc. thereof. In addition, a guanidine derivative has beenreported as the OCT3 activity inhibitor (Non Patent Literature 1described below). However, it has been reported that IC₅₀s of famotidineand cimetidine (histamine H2 receptor antagonists) are 20 μM and 240 μM,respectively, and that IC₅₀s of ramosetron and granisetron (setron-basedcompounds) are both 100 μM or less.

Meanwhile, WO 2005/084707 A (Patent Literature 1) discloses atherapeutic agent for mental disorder, containing a substancesuppressing expression of an organic cation transporter OCT3 gene as anactive component. US 2007/0136828 (Patent Literature 2) discloses atherapeutic agent for depression by inhibiting a function of the OCT3,containing an antisense nucleic acid of the OCT3 gene. WO 2009/134877 A(Patent Literature 3) discloses a therapeutic agent for depression byinhibiting a function of the OCT3, containing an alkylamine-catecholderivative, a quinoline derivative, and a bis-quinoline derivative asactive components. WO 2001/93863 A (Patent Literature 4) discloses atherapeutic agent for depression and symptoms suggesting depression,containing famotidine as an active component. U.S. Pat. No. 6,403,645(Patent Literature 5) discloses a therapeutic agent for depression,containing a transporter Uptake2 (OCT and PMAT) inhibitor as an activecomponent.

According to these literatures, it has been established that depressionand symptoms suggesting depression can be treated by inhibiting theorganic cation transporter OCT3.

These pharmaceutical agents are disadvantageous in view of intracerebraltransferability and nephrotoxicity. Therefore, development of a novelOCT3 activity inhibitor having a completely different basic structurehas been desired. In addition, development of an OCT3 detection agenthas been desired.

A medicine containing an imidazo[1,2-a]pyridine derivative as an activecomponent is known. For example, Zolpidem (registered trademark) is atherapeutic agent for insomnia, which acts on a ω1-type GABA_(A)receptor. Alpidem (registered trademark) is an anxiolytic drug whichacts on a peripheral benzodiazepine receptor. Zolimidin (registeredtrademark) is an antiulcer drug. Olprinone (registered trademark) is atherapeutic agent for acute heart failure, which inhibits PDE3.

CITATION LIST Patent Literatures

-   Patent Literature 1: WO 2005/084707 A-   Patent Literature 2: US 2007/0136828-   Patent Literature 3: WO 2009/134877 A-   Patent Literature 4: WO 2001/93863 A-   Patent Literature 5: U.S. Pat. No. 6,403,645

Non Patent Literatures

-   Non Patent Literature 1: Nies, 2011, Handb Exp Pharmacol., v201, p    105-167 Nies, 2011, Handb Exp Pharmacol., v201, p 105-167-   Non Patent Literature 2: Sata, 2005, J Pharmacol Exp Ther., v315, p    888-895 Sata, 2005, J Pharmacol Exp Ther., v315, p 888-895

SUMMARY OF INVENTION Technical Problem

An object of the present invention is to provide an OCT3 activityinhibitor having a different basic structure from the OCT3 activityinhibitor in the related art.

Another object of the present invention is to provide a therapeuticagent for a disease relating to the OCT3.

Still another object of the present invention is to provide an OCT3detection agent.

Solution to Problem

The present invention is basically based on the finding that animidazopyridine derivative (particularly imidazo[1,2-a]pyridinederivative) has a bonding function to the OCT3 and an OCT3activity-inhibiting function.

A first aspect of the present invention relates to an organic cationtransporter 3 (OCT3) inhibitor containing, as an active component, acompound represented by formula (I), a pharmaceutically acceptable saltthereof, or a pharmaceutically acceptable solvate thereof.

In formula (I), R¹ to R³, R⁵ and R⁶ may be the same or different, andeach represent a hydrogen atom, a halogen atom, a C₁₋₃ alkyl group, aC₁₋₃ alkoxy group, a C₁₋₃ alkylthio group, or a C₁₋₃ halogenoalkylgroup. R⁴ represents any of the groups represented by formulae (II) to(VII).

In formula (II), X² represents a C₁₋₁₀ alkyl group which may have asubstituent, a C₁₋₁₀ alkoxy group which may have a substituent, a C₁₋₁₀alkylthio group which may have a substituent, a C₂₋₁₀ alkenyl groupwhich may have a substituent, or a C₂₋₁₀ alkynyl group which may have asubstituent.

In formula (III), X³ represents a C₁₋₁₀ alkyl group which may have asubstituent, a C₁₋₁₀ alkoxy group which may have a substituent, a C₁₋₁₀alkylthio group which may have a substituent, a C₂₋₁₀ alkenyl groupwhich may have a substituent, or a C₂₋₁₀ alkynyl group which may have asubstituent. Note that a symbol (*) is given to a bonding portion to thecarbon atom (C) adjacent to R⁴ in formula (III).

In formula (VI), X⁴ represents a C₁₋₁₀ alkyl group which may have asubstituent, a C₁₋₁₀ alkoxy group which may have a substituent, a C₁₋₁₀alkylthio group which may have a substituent, a C₂₋₁₀ alkenyl groupwhich may have a substituent, a C₂₋₁₀ alkynyl group which may have asubstituent, or a C₆₋₁₂ aryl group which may have a substituent.

In formula (V), X⁵ represents a C₁₋₁₀ alkyl group which may have asubstituent, a C₁₋₁₀ alkoxy group which may have a substituent, a C₁₋₁₀alkylthio group which may have a substituent, a C₂₋₁₀ alkenyl groupwhich may have a substituent, a C₂₋₁₀ alkynyl group which may have asubstituent, a 5-membered ring group which may have a substituent, or aC₆₋₁₂ aryl group which may have a substituent.

In formula (VI), X⁶ represents a C₁₋₁₀ alkyl group which may have asubstituent, a C₁₋₁₀ alkoxy group which may have a substituent, a C₁₋₁₀alkylthio group which may have a substituent, a C₂₋₁₀ alkenyl groupwhich may have a substituent, a C₂₋₁₀ alkynyl group which may have asubstituent, a 5-membered ring group which may have a substituent, or aC₆₋₁₂ aryl group which may have a substituent.

In formula (VII), X⁷ represents a C₁₋₁₀ alkyl group which may have asubstituent, a C₁₋₁₀ alkoxy group which may have a substituent, a C₁₋₁₀alkylthio group which may have a substituent, a C₂₋₁₀ alkenyl groupwhich may have a substituent, a C₂₋₁₀ alkynyl group which may have asubstituent, a 5-membered ring group which may have a substituent, or aC₆₋₁₂ aryl group which may have a substituent.

A second aspect of the present invention relates to a therapeutic agentfor mental disorder, containing any of the above-described “organiccation transporter 3 (OCT3) inhibitors” as an active component. Morespecifically, this aspect relates to a therapeutic agent for depression,containing any of the above-described organic cation transporter 3(OCT3) inhibitors as an active component.

A third aspect of the present invention relates to an organic cationtransporter 3 (OCT3) detection agent.

Advantageous Effects of Invention

According to the present invention, it is possible to provide an OCT3activity inhibitor having a different basic structure from the OCT3activity inhibitor in the related art.

In addition, the present invention can provide a therapeutic agent for adisease relating to the OCT3.

Furthermore, the present invention can provide an OCT3 detection agent.

DESCRIPTION OF EMBODIMENTS

A first aspect of the present invention relates to an organic cationtransporter 3 (OCT3) inhibitor containing, as an active component, acompound represented by formula (I) (the compound of the presentinvention), a pharmaceutically acceptable salt thereof, or apharmaceutically acceptable solvate thereof. As illustrated in thefollowing formula (I), the compound of the present invention is animidazopyridine derivative. More specifically, the compound of thepresent invention is an imidazo[1,2-a]pyridine derivative.

In formula (I), R¹ to R³, R⁵ and R⁶ may be the same or different, andeach represent a hydrogen atom, a halogen atom, a C₁₋₃ alkyl group, aC₁₋₃ alkoxy group, a C₁₋₃ alkylthio group, or a C₁₋₃ halogenoalkylgroup. Preferable examples of R¹ to R³, R⁵, and R⁶ include a hydrogenatom and a C₁₋₃ alkyl group. Here, the C₁₋₃ alkyl group is preferably amethyl group or an ethyl group.

R⁴ represents any of the groups represented by formulae (II) to (VII).

In formula (II), X² represents a C₁₋₁₀ alkyl group which may have asubstituent, a C₁₋₁₀ alkoxy group which may have a substituent, a C₁₋₁₀alkylthio group which may have a substituent, a C₂₋₁₀ alkenyl groupwhich may have a substituent, a C₂₋₁₀ alkynyl group which may have asubstituent, a C₆₋₁₀ aryl group which may have a substituent, or a C₇₋₁₀aralkyl group which may have a substituent.

In formula (III), X³ represents a C₁₋₁₀ alkyl group which may have asubstituent, a C₁₋₁₀ alkoxy group which may have a substituent, a C₁₋₁₀alkylthio group which may have a substituent, a C₂₋₁₀ alkenyl groupwhich may have a substituent, or a C₂₋₁₀ alkynyl group which may have asubstituent. Note that a symbol (*) is given to a bonding portion to thecarbon atom (C) adjacent to R⁴ in formula (III).

In formula (VI), X⁴ represents a C₁₋₁₀ alkyl group which may have asubstituent, a C₁₋₁₀ alkoxy group which may have a substituent, a C₁₋₁₀alkylthio group which may have a substituent, a C₂₋₁₀ alkenyl groupwhich may have a substituent, a C₂₋₁₀ alkynyl group which may have asubstituent, or a C₆₋₁₂ aryl group which may have a substituent.

In formula (V), X⁵ represents a C₁₋₁₀ alkyl group which may have asubstituent, a C₁₋₁₀ alkoxy group which may have a substituent, a C₁₋₁₀alkylthio group which may have a substituent, a C₂₋₁₀ alkenyl groupwhich may have a substituent, a C₂₋₁₀ alkynyl group which may have asubstituent, a 5-membered ring group which may have a substituent, or aC₆₋₁₂ aryl group which may have a substituent.

In formula (VI), X⁶ represents a C₁₋₁₀ alkyl group which may have asubstituent, a C₁₋₁₀ alkoxy group which may have a substituent, a C₁₋₁₀alkylthio group which may have a substituent, a C₂₋₁₀ alkenyl groupwhich may have a substituent, a C₂₋₁₀ alkynyl group which may have asubstituent, a 5-membered ring group which may have a substituent, or aC₆₋₁₂ aryl group which may have a substituent.

In formula (VII), X⁷ represents a C₁₋₁₀ alkyl group which may have asubstituent, a C₁₋₁₀ alkoxy group which may have a substituent, a C₁₋₁₀alkylthio group which may have a substituent, a C₂₋₁₀ alkenyl groupwhich may have a substituent, a C₂₋₁₀ alkynyl group which may have asubstituent, a 5-membered ring group which may have a substituent, or aC₆₋₁₂ aryl group which may have a substituent.

The organic cation transporter 3 (OCT3) inhibitor inhibits an activityof the OCT3. The OCT3 activity-inhibiting function can be measured by amethod described in Examples.

The pharmaceutically acceptable salt indicates a derivative of thedisclosed compound, modified by forming an acidic or basic salt of aparent compound. Examples of the pharmaceutically acceptable salt arenot limited to, but include an inorganic acid salt of a basic residuesuch as amine and an organic acid salt thereof, and an alkali salt of anacidic residue such as carboxylic acid and an organic salt thereof.Examples of the pharmaceutically acceptable salt include a normalnontoxic salt of the parent compound and a quaternary ammonium saltthereof, generated from a nontoxic inorganic or organic acid. Such anormal nontoxic salt includes a salt derived from an inorganic acid anda salt prepared from an organic acid. Examples of the inorganic acidinclude hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamicacid, phosphoric acid, and nitric acid. Examples of the organic acidinclude acetic acid, propionic acid, succinic acid, glycolic acid,stearic acid, lactic acid, malic acid, tartaric acid, citric acid,ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid,phenylacetic acid, glutamic acid, benzoic acid, salicylic acid,sulfanilic acid, 2-acetoxy benzoic acid, fumaric acid, toluenesulfonicacid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, andisethionic acid.

The pharmaceutically acceptable salt of the compound provided herein issynthesized by a usual chemical method from the parent compoundcontaining a basic or acidic moiety. In general, for example, such saltsare prepared by causing these compounds in a form of a free acid or afree base to react with a base or an acid in an appropriatestoichiometric amount in water, an organic solvent, or a mixture ofthese two kinds of solvents. In general, a nonaqueous medium such asether, ethyl acetate, ethanol, isopropanol, or acetonitrile ispreferable. Suitable salts are listed in “Remington's PharmaceuticalSciences”, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p.1418. Its disclosure is incorporated here by reference.

In the pharmaceutically acceptable solvate, a solvent is solvated to atarget compound. An example of solvation is hydration. The compound ofthe present invention includes a compound containing a hydroxyl group,an amide group, or the like, which can form a hydrate with water in theatmosphere.

The “C₁₋₁₀ alkyl group which may have a substituent” is a C₁₋₁₀ alkylgroup having one or more substituents selected from the followingsubstituent group A. The C₁₋₁₀ alkyl group in the C₁₋₁₀ alkyl groupwhich may have a substituent is a linear alkyl group having 1 to 10carbon atoms, a branched alkyl group having 3 to 10 carbon atoms, or acyclic alkyl group having 3 to 10 carbon atoms. Examples of the linearalkyl group include a methyl group, an ethyl group, a propyl group, abutyl group, a pentyl group, a hexyl group, a heptyl group, an octylgroup, a nonyl group, and a decyl group. Examples of the branched alkylgroup include an isopropyl group, an isobutyl group, a 1-methylpropylgroup, a t-butyl group, a 1-methylbutyl group, a 2-methylbutyl group, a3-methylbutyl group, a 1-ethylpropyl group, a 1,1-dimethylpropyl group,a 2,2-dimethylpropyl group, a 1,2-dimethylpropyl group, a 1-methylpentylgroup, a 2-methylpentyl group, a 3-methylpentyl group, a 4-methylpentylgroup, a 1-ethylbutyl group, a 2-ethylbutyl group, a 1,1-dimethylbutylgroup, a 1,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a2,2-dimethylbutyl group, a 2,3-dimethylbutyl group, a 3,3-dimethylbutylgroup, a 5-methylhexyl group, a 3-ethylpentyl group, a 1-propylbutylgroup, a 1,4-dimethylpentyl group, a 3,4-dimethylpentyl group, a1,2,3-trimethylbutyl group, a 1-isopropylbutyl group, a4,4-dimethylpentyl group, a 5-methylpentyl group, a 6-methylheptylgroup, a 4-ethylhexyl group, a 2-propylpentyl group, a 2,5-dimethylhexylgroup, a 4,5-dimethylhexyl group, a 2-ethyl-3-methylpentyl group, a1,2,4-trimethylpentyl group, a 2-methyl-1-isopropylbutyl group, a3-methyloctyl group, a 2,5-dimethylheptyl group, a1-(1-methylpropyl)-2-methylbutyl group, a 1,4,5-trimethylhexyl group, a1,2,3,4-tetramethylpentyl group, a 7-methyloctyl group, a 6-methylnonylgroup, 8-methylnonyl group, a 5-ethyl-2-methylheptyl group, a2,3-dimethyl-1-(1-methylpropyl)butyl group, a cyclopropylmethyl group, a2-(cyclopropyl)ethyl group, a 3,7-dimethyloctyl group, a3-(cyclobutyl)pentyl group, a cyclopentylmethyl group, and acyclohexylmethyl group. Examples of the cyclic alkyl group include acyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexylgroup, a cycloheptyl group, and a cyclooctyl group. In the C₁₋₁₀ alkylgroup, a C₁₋₆ alkyl group is preferable, and a C₁₋₃ alkyl group is morepreferable. Examples of the C₁₋₆ alkyl group include a methyl group, anethyl group, a n-propyl group, an isopropyl group, a n-butyl group, anisobutyl group, a sec-butyl group, a tert-butyl group, a n-pentyl group,an isopentyl group, a neopentyl group, a tert-pentyl group, a1-methylbutyl group, a 2-methylbutyl group, a 1,2-dimethylpropyl group,a 1-ethylpropyl group, a n-hexyl group, an isohexyl group, a1-methylpentyl group, a 2-methylpentyl group, a 3-methylpentyl group, a1,1-dimethylbutyl group, a 1,2-dimethylbutyl group, a 2,2-dimethylbutylgroup, a 1-ethylbutyl group, a 1,1,2-trimethylpropyl group, a1,2,2-trimethylpropyl group, a 1-ethyl-2-methylpropyl group, and a1-ethyl-1-methylpropyl group.

The “C₁₋₁₀ alkoxy group which may have a substituent” is a C₁₋₁₀ alkoxygroup having one or more substituents selected from the followingsubstituent group A. Examples of the C₁₋₁₀ alkoxy group in the C₁₋₁₀alkoxy group which may have a substituent include a group in which agroup represented by —O— is bonded to an end of the above-describedC₁₋₁₀ alkyl group. Specific examples thereof include a methoxy group, anethoxy group, and a propyloxy group.

The “C₁₋₁₀ alkylthio group which may have a substituent” is a C₁₋₁₀alkylthio group having one or more substituents selected from thefollowing substituent group A. Examples of the C₁₋₁₀ alkylthio group inthe C₁₋₁₀ alkylthio group which may have a substituent include a groupin which a group represented by —S— is bonded to an end of theabove-described C₁₋₁₀ alkyl group.

The “C₂₋₁₀ alkenyl group which may have a substituent” is a C₂₋₁₀alkenyl group having one or more substituents selected from thefollowing substituent group A. The C₂₋₁₀ alkenyl group in the C₂₋₁₀alkenyl group which may have a substituent is a linear alkenyl grouphaving 2 to 10 carbon atoms and at least one double bond, a branchedalkenyl group having 3 to 10 carbon atoms, or a cyclic alkenyl grouphaving 5 to 10 carbon atoms. Examples thereof include a vinyl group, anallyl group, a 3-butenyl group, a 4-pentenyl group, a 5-hexenyl group, a6-heptenyl group, a 7-octenyl group, a 8-nonenyl (noneyl) group, a9-decenyl group, a 1-methyl-2-butenyl group, a 2-methyl-2-butenyl group,a 2-methyl-3-butenyl group, a 2-pentenyl group, a 2-methyl-2-hexenylgroup, and a 2-cyclopentenyl group. In the C₂₋₁₀ alkenyl group, a C₂₋₆alkenyl group is preferable, and a C₂₋₃ alkenyl group is morepreferable.

The “C₂₋₁₀ alkynyl group which may have a substituent” is a C₂₋₁₀alkynyl group having one or more substituents selected from thefollowing substituent group A. The alkynyl group is a monovalent grouphaving at least one triple bond (two adjacent SP carbon atoms). Examplesof the C₂₋₁₀ alkynyl group include an ethynyl group, a 1-propynyl group,a propargyl group, and a 3-butynyl group. The C₂₋₁₀ alkynyl group ispreferably a C₂₋₆ alkynyl group, more preferably a C₂₋₅ alkynyl group,still more preferably a C₂₋₄ alkynyl group, and further still morepreferably a C₂₋₃ alkynyl group.

The “C₆₋₁₂ aryl group which may have a substituent” is a C₆₋₁₂ arylgroup having one or more substituents selected from the followingsubstituent group A. The C₆₋₁₂ aryl group may be a heteroaryl group. TheC₆₋₁₂ aryl group in the C₆₋₁₂ aryl group which may have a substituentgroup is an aromatic carbocyclic group or an aromatic heterocyclicgroup. Examples of the aromatic carbocyclic group and the aromaticheterocyclic group as the C₆₋₁₂ aryl group include a phenyl group, a2-fluorophenyl group, a 3-fluorophenyl group, a 4-fluorophenyl group, a4-chlorophenyl group, a 3,4-difluorophenyl group, a 2,4-difluorophenylgroup, a 2-trifluoromethylphenyl group, a 3-trifluorophenylmethyl group,a 4-trifluoromethylphenyl group, a 4-methoxyphenyl group, a4-methanesulfonylphenyl group, a 3-fluoro-4-methoxyphenyl group, anaphthyl group, a pyridinyl group, a 3-trifluoromethylpyridin-6-ylgroup, a 2-trifluoromethylpyridin-5-yl group, a 2-fluoropyridin-5-ylgroup, a 3-fluoropyridin-6-yl group, a 3-chloropyridin-6-yl group, a2-methoxypyridin-5-yl group, a 3-methoxypyridin-6-yl group, a2-difluoromethoxypyridin-5-yl group, a 3-difluoromethoxypyridin-6-ylgroup, a 2-pyrazinyl group, a 2-pyrimidinyl group, a5-trifluoromethylpyrimidin-2-yl group, a 2-trifluoromethylpyrimidin-5-ylgroup, a 3-trifluoromethyl-6-pyridinyl group, a 3-pyridazinyl group, apyrrol-1-yl group, a 2-imidazolyl group, a 1-imidazolyl group, atriazolyl group, a 3-isoxazolyl group, a 1,3,4-oxadiazol-2-yl group, a5-methyl-1,3,4-oxadiazol-2-yl group, a 2-thiazolyl group, a thiadiazolylgroup, a tetrazolyl group, a 2-methylpyridin-5-yl group, a3-methylpyridin-6-yl group, a 2-difluoromethylpyridin-5-yl group, a3-difluoromethylpyridin-6-yl group, a 2-trifluoromethoxypyridin-5-ylgroup, and a 3-trifluoromethoxypyridin-6-yl group.

Substituent Group A

A halogen atom, a cyano group, a hydroxyl group, an amino group, a nitrogroup, a C₁₋₆ alkyl group, a C₃₋₆ cycloalkyl group, a C₁₋₆ alkyl groupwhich may be substituted with a fluorine atom, a C₁₋₆ alkyl group whichmay be substituted with a hydroxyl group, a C₁₋₆ alkyloxy group whichmay be substituted with a fluorine atom, a mono C₁₋₆ alkylamino group, adi C₁₋₆ alkylamino group, a C₁₋₆ alkyloxy C₁₋₆ alkyl group, a C₁₋₆alkyloxycarbonyl group, a (C₁₋₆ alkyloxycarbonyl)amino group, a (C₁₋₆alkyloxycarbonyl)C₁₋₆ alkylamino group, a C₁₋₆ alkylcarbonyl group, aC₁₋₆ alkylcarbonyloxy group, a C₁₋₆ alkylcarbonylamino group, a (C₁₋₆alkylcarbonyl)C₁₋₆ alkylamino group, a mono C₁₋₆ alkylcarbamoyl group, adi C₁₋₆ alkylcarbamoyl group, a mono C₁₋₆ alkylcarbamoylamino group, adi C₁₋₆ alkylcarbamoylamino group, a (mono C₁₋₆ alkylcarbamoyl)C₁₋₆alkylamino group, a (di C₁₋₆ alkyl carbamoyl)C₁₋₆ alkylamino group, amono C₁₋₆ alkylcarbamoyloxy group, a di C₁₋₆ alkylcarbamoyloxy group, aC₁₋₆ alkylsulfonyl group, a C₁₋₆ alkylsulfonylamino group, a C₁₋₆alkylsulfonyl (C₁₋₆ alkyl)amino group, a mono C₁₋₆ alkylsulfamoyl group,a di C₁₋₆ alkylsulfamoyl group, a (mono C₁₋₆ alkylsulfamoyl)amino group,a (di C₁₋₆ alkylsulfamoyl)amino group, a mono C₁₋₆ alkylsulfamoyl (C₁₋₆alkyl)amino group, a di C₁₋₆ alkylsulfamoyl (C₁₋₆ alkyl)amino group, a 3to 8-membered heterocycloalkyl group, an aromatic carbocyclic group, andan aromatic heterocyclic group.

Examples of the halogen atom include a fluorine atom, a chlorine atom, abromine atom, and an iodine atom.

The “C₃₋₆ cycloalkyl group” is a cycloalkyl group having 3 to 6 carbonatoms, and specific examples thereof include a cyclopropyl group, acyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

The “C₁₋₆ alkyl group which may be substituted with a fluorine atom”includes a C₁₋₆ alkyl group and a C₁₋₆ alkyl group in which some or allof the hydrogen atoms in the C₁₋₆ alkyl group are substituted withfluorine atoms. Specific examples of the latter C₁₋₆ alkyl groupsubstituted with fluorine atoms include a fluoromethyl group, adifluoromethyl group, a trifluoromethyl group, and a 1,2-difluoroethylgroup.

The “C₁₋₆ alkyl group which may be substituted with a hydroxyl group”includes a C₁₋₆ alkyl group and a C₁₋₆ alkyl group in which some of thehydrogen atoms in the C₁₋₆ alkyl group are substituted with hydroxylgroups. Specific examples of the latter C₁₋₆ alkyl group substitutedwith hydroxyl groups include a hydroxymethyl group, a 2-hydroxyethylgroup, and a 3-hydroxypropyl group.

The “C₁₋₆ alkyloxy group which may be substituted with a fluorine atom”includes a group in which a C₁₋₆ alkyl group or a C₁₋₆ alkyl groupsubstituted with a fluorine atom is bonded to an oxygen atom. Specificexamples of the C₁₋₆ alkyloxy group include a methoxy group, an ethoxygroup, a n-propyloxy group, an isopropyloxy group, a n-butyloxy group,an isobutoxy group, a tert-butoxy group, and a n-pentyloxy group.Specific examples of the C₁₋₆ alkyloxy group substituted with a fluorineatom include a fluoromethoxy group, a difluoromethoxy group, atrifluoromethoxy group, and a 1,2-difluoroethoxy group.

The “mono C₁₋₆ alkylamino group” is a group in which one hydrogen atomin an amino group is substituted with a C₁₋₆ alkyl group. Specificexamples thereof include a methylamino group, an ethylamino group, an-propylamino group, an isopropylamino group, a n-butylamino group, asec-butylamino group, and a tert-butylamino group.

The “di C₁₋₆ alkylamino group” is a group in which two hydrogen atoms inan amino group are substituted with C₁₋₆ alkyl groups. Specific examplesthereof include a dimethylamino group, a diethylamino group, anethylmethylamino group, a di (n-propyl)amino group, a methylpropylaminogroup, and a diisopropylamino group.

The “C₁₋₆ alkyloxy C₁₋₆ alkyl group” is a group in which one hydrogenatom in a C₁₋₆ alkyl group is substituted with a C₁₋₆ alkyloxy group.Specific examples thereof include a methoxymethyl group, an ethoxymethylgroup, a n-propyloxymethyl group, an ethoxymethyl group, and anethoxyethyl group.

The “C₁₋₆ alkyloxycarbonyl group” is a group in which a C₁₋₆ alkyloxygroup is bonded to a carbonyl group. Specific examples thereof include amethoxycarbonyl group, an ethoxycarbonyl group, a n-propyloxycarbonylgroup, an isopropyloxycarbonyl group, a n-butyloxycarbonyl group, anisobutoxycarbonyl group, a tert-butoxycarbonyl group, and an-pentyloxycarbonyl group.

The “(C₁₋₆ alkyloxycarbonyl)amino group” is a group in which a C₁₋₆alkyloxycarbonyl group is bonded to an amino group. Specific examplesthereof include a methoxycarbonylamino group, an ethoxycarbonylaminogroup, a n-propyloxycarbonylamino group, an isopropyloxycarbonylaminogroup, a n-butoxycarbonylamino group, an isobutoxycarbonylamino group, atert-butoxycarbonylamino group, and a n-pentyloxycarbonylamino group.

The “(C₁₋₆ alkyloxycarbonyl)C₁₋₆ alkyl amino group” is a group in whicha hydrogen atom bonded to a nitrogen atom in a mono C₁₋₆ alkylaminogroup is substituted with a C₁₋₆ alkyloxycarbonyl group. Specificexamples thereof include a (methoxycarbonyl)methylamino group, an(ethoxycarbonyl)methylamino group, and a(n-propyloxycarbonyl)methylamino group.

The “C₁₋₆ alkylcarbonyl group” is a group in which a C₁₋₆ alkyl group isbonded to a carbonyl group. Specific examples thereof include an acetylgroup, a propionyl group, a butyryl group, an isobutyryl group, avaleryl group, an isovaleryl group, and a pivaloyl group.

The “C₁₋₆ alkylcarbonyloxy group” is a group in which a C₁₋₆alkylcarbonyl group is bonded to an oxygen atom. Specific examplesthereof include an acetoxy group, a propionyloxy group, a valeryloxygroup, an isovaleryloxy group, and a pivaloyloxy group.

The “C₁₋₆ alkylcarbonylamino group” is a group in which one hydrogenatom in an amino group is substituted with a C₁₋₆ alkylcarbonyl group.Specific examples thereof include an acetamide group, a propionylaminogroup, an isobutyrylamino group, a valerylamino group, anisovalerylamino group, and a pivaloylamino group.

The “(C₁₋₆ alkylcarbonyl)C₁₋₆ alkylamino group” is a group in which ahydrogen atom bonded to a nitrogen atom in a mono C₁₋₆ alkylamino groupis substituted with a C₁₋₆ alkylcarbonyl group. Specific examplesthereof include a (methylcarbonyl)methlyamino group, an(ethylcarbonyl)methylamino group, and a (n-propylcarbonyl)methylaminogroup.

The “mono C₁₋₆ alkylcarbamoyl group” is a group in which one hydrogenatom in a carbamoyl group is substituted with a C₁₋₆ alkyl group.Specific examples thereof include a methylcarbamoyl group, anethylcarbamoyl group, a n-propylcarbamoyl group, an isopropylcarbamoylgroup, a n-butylcarbamoyl group, a sec-butylcarbamoyl group, and atert-butylcarbamoyl group.

The “di C₁₋₆ alkylcarbamoyl group” is a group in which two hydrogenatoms in a carbamoyl group are substituted with C₁₋₆ alkyl groups.Specific examples thereof include a dimethylcarbamoyl group, adiethylcarbamoyl group, an ethylmethylcarbamoyl group, a di(n-propyl)carbamoyl group, a methylpropylcarbamoyl group, and adiisopropylcarbamoyl group.

The “mono C₁₋₆ alkylcarbamoylamino group” is a group in which onehydrogen atom in an amino group is substituted with a C₁₋₆alkylcarbamoyl group. Specific examples thereof include amethylcarbamoylamino group, an ethylcarbamoylamino group, an-propylcarbamoylamino group, an isopropylcarbamoylamino group, an-butylcarbamoylamino group, a sec-butylcarbamoylamino group, and atert-butylcarbamoylamino group.

The “di C₁₋₆ alkylcarbamoylamino group” is a group in which one hydrogenatom in an amino group is substituted with a di C₁₋₆ alkylcarbamoylgroup. Specific examples thereof include a dimethylcarbamoylamino group,a diethylcarbamoylamino group, a di (n-propyl)carbamoylamino group, adiisopropylcarbamoylamino group, a di (n-butyl)carbamoylamino group, adi (sec-butyl)carbamoylamino group, and a di (tert-butyl)carbamoylaminogroup.

The “(mono C₁₋₆ alkylcarbamoyl)C₁₋₆ alkylamino group” is a group inwhich a hydrogen atom bonded to a nitrogen atom in a mono C₁₋₆alkylamino group is substituted with a mono C₁₋₆ alkylcarbamoyl group.Specific examples thereof include a (mono methylcarbamoyl)methlyaminogroup, a (mono ethylcarbamoyl)methylamino group, and a [mono(n-propyl)carbamoyl]methylamino group.

The “(di C₁₋₆ alkylcarbamoyl)C₁₋₆ alkylamino group” is a group in whicha hydrogen atom bonded to a nitrogen atom in a mono C₁₋₆ alkylaminogroup is substituted with a di C₁₋₆ alkylcarbamoyl group. Specificexamples thereof include a (dimethylcarbamoyl)methlyamino group, a(diethylcarbamoyl)methylamino group, and a[di(n-propyl)carbamoyl]methylamino group.

The “mono C₁₋₆ alkylcarbamoyloxy group” is a group in which a C₁₋₆alkylcarbamoyl group is bonded to an oxygen atom. Specific examplesthereof include a methylcarbamoyloxy group, an ethylcarbamoyloxy group,a n-propylcarbamoyloxy group, an isopropylcarbamoyloxy group, an-butylcarbamoyloxy group, a sec-butylcarbamoyloxy group, and atert-butylcarbamoyloxy group.

The “di C₁₋₆ alkylcarbamoyloxy group” is a group in which a di C₁₋₆alkylcarbamoyl group is bonded to an oxygen atom. Specific examplesthereof include a dimethylcarbamoyloxy group, a diethylcarbamoyloxygroup, an ethylmethylcarbamoyloxy group, a di(n-propyl)carbamoyloxygroup, a methylpropylcarbamoyloxy group, and a diisopropylcarbamoyloxygroup.

The “C₁₋₆ alkylsulfonyl group” is a group in which a C₁₋₆ alkyl group isbonded to a sulfonyl group. Specific examples thereof include amethylsulfonyl group, an ethylsulfonyl group, a n-propylsulfonyl group,an isopropylsulfonyl group, a n-butylsulfonyl group, a sec-butylsulfonylgroup, and a tert-butylsulfonyl group.

The “C₁₋₆ alkylsulfonylamino group” is a group in which one hydrogenatom in an amino group is substituted with a C₁₋₆ alkylsulfonyl group.Specific examples thereof include a methylsulfonylamino group, anethylsulfonylamino group, a n-propylsulfonylamino group, anisopropylsulfonylamino group, a n-butylsulfonylamino group, asec-butylsulfonylamino group, and a tert-butylsulfonylamino group.

The “C₁₋₆ alkylsulfonyl(C₁₋₆ alkyl)amino group” is a group in which ahydrogen atom bonded to a nitrogen atom in a “C₁₋₆ alkylamino group” issubstituted with a C₁₋₆ alkylsulfonyl group. Specific examples thereofinclude a methylsulfonyl(methyl)amino group, anethylsulfonyl(methyl)amino group, and a (n-propyl)sulfonyl(methyl)aminogroup.

The “mono C₁₋₆ alkylsulfamoyl group” is a group in which a C₁₋₆ alkylgroup is bonded to a sulfamoyl group. Specific examples thereof includea monomethylsulfamoyl group, a monoethylsulfamoyl group, amono(n-propyl)sulfamoyl group, a monoisopropylsulfamoyl group, amono(n-butyl)sulfamoyl group, a mono(sec-butyl)sulfamoyl group, and amono(tert-butyl)sulfamoyl group.

The “di C₁₋₆ alkylsulfamoyl group” is a group in which a di C₁₋₆ alkylgroup is bonded to a sulfamoyl group. Specific examples thereof includea dimethylsulfamoyl group, a diethylsulfamoyl group, adi(n-propyl)sulfamoyl group, a diisopropylsulfamoyl group, adi(n-butyl)sulfamoyl group, a di(sec-butyl)sulfamoyl group, and a di(tert-butyl)sulfamoyl group.

The “(mono C₁₋₆ alkylsulfamoyl)amino group” is a group in which onehydrogen atom in an amino group is substituted with a mono C₁₋₆alkylsulfamoyl group. Specific examples thereof include a(monomethylsulfamoyl)amino group, a (monoethylsulfamoyl)amino group, a[mono(n-propyl)sulfamoyl]amino group, a (monoisopropylsulfamoyl)aminogroup, a [mono(n-butyl)sulfamoyl]amino group, a[mono(sec-butyl)sulfamoyl]amino group, and a (tert-butylsulfamoyl)aminogroup.

The “(di C₁₋₆ alkylsulfamoyl)amino group” is a group in which onehydrogen atom in an amino group is substituted with a di C₁₋₆alkylsulfamoyl group. Specific examples thereof include a(dimethylsulfamoyl)amino group, a (diethylsulfamoyl)amino group, an(ethylmethylsulfamoyl)amino group, a [di(n-propyl)sulfamoyl]amino group,a (methylpropylsulfamoyl)amino group, and a (diisopropylsulfamoyl)aminogroup.

The “mono C₁₋₆ alkylsulfamoyl(C₁₋₆ alkyl)amino group” is a group inwhich a hydrogen atom bonded to a nitrogen atom in a “mono C₁₋₆alkylamino group” is substituted with a mono C₁₋₆ alkylsulfamoyl group.Specific examples thereof include a monomethylsulfamoyl(methly)aminogroup, a monoethylsulfamoyl(methyl)amino group, and a mono(n-propyl)sulfamoyl(methyl)amino group.

The “di C₁₋₆ alkylsulfamoyl(C₁₋₆ alkyl)amino group” is a group in whicha hydrogen atom bonded to a nitrogen atom in a “mono C₁₋₆ alkylaminogroup” is substituted with a di C₁₋₆ alkylsulfamoyl group. Specificexamples thereof include a dimethylsulfamoyl(methly)amino group, adiethylsulfamoyl(methyl)amino group, and adi(n-propyl)sulfamoyl(methyl)amino group.

Examples of the “3 to 8-membered heterocycloalkyl group” include anazetidinyl group, a pyrrolidinyl group, a piperidinyl group, apiperazinyl group, an imidazolidinyl group, a tetrahydrofuranyl group, atetrahydropyranyl group, a morpholinyl group, a 1-thia-4-azocyclohexylgroup, and a 2,5-diazabicyclo[2.2.2]octanyl group.

Preferable Examples of the compound of the present invention as a firstgroup are as follows. That is, a compound represented by formula (I), inwhich R¹, R², R³, R⁵, and R⁶ each represent a hydrogen atom or a methylgroup, and R⁴ represents a group represented by formula (II). In thisembodiment, R¹, R³, R⁵, and R⁶ each preferably represent a hydrogenatom, and R² preferably represents a methyl group.

In formula (II), X² represents a group represented by —Y²¹-Y²²-Y²³ or—Y²¹-Y²²(—Y²³Y²⁴). Y²¹ represents a linear or branched C₁₋₅ alkylenegroup. Y²² represents a single bond, an oxygen atom, a sulfur atom, or agroup represented by SO₂ (—S(═O)₂—).

Y²³ and Y²⁴ may be the same or different, and each represent:

a hydrogen atom;

a C₁₋₅ alkyl group;

a C₃₋₆ cycloalkyl group;

a pyrrolidinyl group which may be substituted with a methyl group, agroup represented by ═O (carbonyl group), or a halogen atom;

a thiazolidinyl group which may be substituted with a methyl group, agroup represented by ═O (carbonyl group), or a halogen atom;

a phenyl group bonded to a linear or branched C₁₋₅ alkyl group;

a phenyl group substituted with a C₁₋₅ alkoxy group bonded to a linearor branched C₁₋₅ alkyl group;

a pyrrolidinyl group substituted with a halogen atom, a nitro group, aC₁₋₅ alkyl group, C₁₋₅ alkoxy group, C₁₋₅ halgenoalkyl group, C₁₋₅halgenoalkoxy group, a pyrrolidinyl group, or a group represented by ═O(carbonyl group); or

a benzimidazolyl (benzomidazolyl) group.

In formula (II), X² may represent a group represented by —Y²⁵(Y²⁶)-Y²⁷.

Y²⁵ represents a phenyl group in which one to three hydrogen atoms maybe substituted with a halogen atom, a nitro group, a C₁₋₅ alkyl group, aC₁₋₅ alkoxy group, a C₁₋₅ halgenoalkyl group, a C₁₋₅ halgenoalkoxygroup, a pyrrolidinyl group, or a group represented by ═O.

Y²⁶ represents a pyrrolidinyl group which may substituted with ahydrogen atom, a phenyl group, a C₃₋₅ cycloalkyl group, or a C₁₋₅ alkylgroup, or a pyrrole group which may be substituted with a C₁₋₅ alkylgroup.

Y²⁷ represents:

a hydrogen atom;

a halogen atom;

a C₃₋₅ cycloalkyl group;

a pyrrolidinyl group bonded to a linear or branched C₁₋₅ alkyl group;

a piperidinyl group bonded to a linear or branched C₁₋₅ alkyl group;

a dioxolanyl group;

an imidazolyl (midazolyl) group;

a group represented by —C(═O)—CH₃;

a group represented by —C(═O)—NH₂;

a group represented by —C(═O)—NC₅H₁₀;

a group represented by —S(O₂)NHCH₃;

a group represented by —S(O₂)NHC₃H₇;

a group represented by —NC(═O)OCH₃;

a group represented by —NC(═O)C₃H₅;

a group represented by —NC(═O)C₃H₇; or

a group represented by

In preferable compounds of the first group, in formula (I), R¹, R², R³,R⁵ and R⁶ each represent a hydrogen atom or a methyl group, and R⁴represents a group represented by formula (II). In formula (II), X²represents any of the groups represented by the following formulae (1-1)to (1-26). In this embodiment, R¹, R³, R⁵, and R⁶ each preferablyrepresent a hydrogen atom, and R² preferably represents a methyl group.Note that, in formulae (1-5), (1-8), (1-9), (1-10), (1-12), (1-14),(1-19), (1-22), (1-24), and (1-25), a bonding site is clearly indicatedby giving a symbol (*) to a bonding portion to a nitrogen atom (N)adjacent to X².

In a second group of the compound of the present invention, R¹, R², R³,R⁵ and R⁶ each represent a hydrogen atom or a methyl group, and R⁴represents a group represented by formula (III). In formula (III), X³represents a group represented by the following formula (2-1) or (2-2).In this embodiment, R¹, R³, R⁵, and R⁶ each preferably represent ahydrogen atom, and R² preferably represents a methyl group.

In a third group of the compound of the present invention, in formula(I), R¹, R², R³, R⁵ and R⁶ each represent a hydrogen atom or a methylgroup, and R⁴ represents a group represented by formula (IV). In formula(IV), X⁴ represents any of the groups represented by the followingformulae (3-1) to (3-4). In this embodiment, R¹, R³, R⁵, and R⁶ eachpreferably represent a hydrogen atom, and R² preferably represents amethyl group.

In a fourth group of the compound of the present invention, in formula(I), R¹, R², R³, R⁵ and R⁶ each represent a hydrogen atom or a methylgroup, and R⁴ represents a group represented by formula (V). In formula(V), X⁵ represents any of the groups represented by the followingformulae (4-1), (5-1), (5-2), and (6-1).

In this embodiment, the following compounds are preferable. That is:

a compound in which R¹ represents a methyl group, R², R³, R⁵, and R⁶each represent a hydrogen atom, and X⁵ represents a group represented byformula (4-1) in formula (V);

a compound in which R¹, R², R⁵, and R⁶ each represent a hydrogen atom,R³ represents a methyl group, and X⁵ represents a group represented byformula (5-1) or (5-2) in formula (V); or

a compound in which R¹, R², R³, R⁵, and R⁶ each represent a hydrogenatom, and X⁵ represents any of the groups represented by formula (6-1)in formula (V). Note that, in formulae (4-1), (5-2), and (6-1), abonding site is clearly indicated by giving a symbol (*) to a bondingportion to a sulfur atom (S) adjacent to X⁵.

In a fifth group of the compound of the present invention, in formula(I), R¹, R², R³, R⁵ and R⁶ each represent a hydrogen atom or a methylgroup, and R⁴ represents a group represented by formula (VI). In formula(VI), X⁶ represents any of groups represented by the following formula(7-1) or (7-4). In this embodiment, R¹, R², R³, R⁵ and R⁶ eachpreferably represent a hydrogen atom. Note that, in formula (7-4), abonding site is clearly indicated by giving a symbol (*) to a bondingportion to a carbon atom (C) adjacent to X⁶.

The above-described formula (7-1) includes stereoisomers, which areincluded in the compound of the present invention.

In a sixth group of the compound of the present invention, in formula(I), R¹, R², R³, R⁵ and R⁶ each represent a hydrogen atom or a methylgroup, and R⁴ represents a group represented by formula (VII). Informula (VII), X⁷ represents any of groups represented by the followingformula (8-1) or (8-2). In this embodiment, R¹, R², R³, R⁵ and R⁶ eachpreferably represent a hydrogen atom.

An OCT3 activity inhibitor including the compound of the presentinvention can be manufactured in a similar manner to a method disclosedin Re-publication of PCT International Publication No. 2005/084707.Examples of the activity of the OCT3 include a transport activity ofdopamine, serotonin, noradrenaline, dopamine neurotoxin MPP+, astimulant, or the like. These activities can be measured by a methodwell known to a person skilled in the art.

The OCT3 activity inhibitor including the compound of the presentinvention is effective in a treatment of a disease (depression andsymptoms suggesting depression) relating to the OCT3. As describedbelow, it has been demonstrated that depression and symptoms suggestingdepression can be treated by inhibiting the organic cation transporterOCT3. For example, the prior literature (Kitaichi. et al., NeurosciLett. 2005 Jul. 1-8; 382 (1-2): 195-200) reports that an antidepressanteffect is exhibited in a forced swimming test by suppressing expressionof an OCT3 gene in a mouse with an antisense or knock-out technology. Onthe other hand, the present OCT3 inhibitor is presumed to have an effectsimilar to suppressing the expression of the OCT3 gene because this OCT3inhibitor inhibits a function of OCT3 protein.

As demonstrated in Examples, the compound of the present invention, apharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate thereof has the OCT3 inhibitory activity. Therefore,the present invention also provides a therapeutic agent for depressionand symptoms suggesting depression, containing the above-described OCT3inhibitor as an active component. The depression and symptoms suggestingdepression include physical depression, unipolar depression, psychogenicfunctional disease, atypical depression, dysthymia, bipolar affectivedisease, seasonal depression, and persistent mood disorder.

The compound of the present invention can be administered orally orparenterally, and can be formulated in a form suitable foradministration thereof. In order to use the compound of the presentinvention clinically, it is also possible to administer the compoundafter the compound is variously formulated by adding a pharmaceuticallyacceptable carrier according to an administration form thereof. As thecarrier in this case, various additives in the related art of thepharmaceutical field can be used. Examples thereof include gelatin,lactose, sucrose, titanium oxide, starch, crystalline cellulose,hydroxypropylmethyl cellulose, carboxymethyl cellulose, corn starch,microcrystalline wax, white petrolatum, magnesium metasilicatealuminate, calcium phosphate anhydride, citric acid, trisodium citrate,hydroxypropyl cellulose, sorbitol, sorbitan fatty acid ester,polysorbate, sucrose fatty acid ester, polyoxyethylene, hardened castoroil, polyvinyl pyrrolidone, magnesium stearate, light anhydrous silicicacid, talc, vegetable oil, benzyl alcohol, gum arabic, propylene glycol,polyalkylene glycol, cyclodextrin, and hydroxypropyl cyclodextrin.

Examples of a dosage form to be formulated as a mixture of thesecarriers and the compound of the present invention include a tablet, acapsule, a granule, a solid preparation such as powder or a suppository,and a liquid preparation such as a syrup, an elixir, or an injection.These dosage forms can be prepared according to a method in the relatedart of the pharmaceutical field. Note that a liquid preparation may bedissolved or suspended in water or another appropriate medium when beingused. Particularly, the injection may be dissolved or suspended inphysiological saline or a glucose solution if necessary, and a buffer ora preservative may be further added thereto.

These preparations can contain the compound of the present invention in1.0 to 100 wt %, preferably in 1.0 to 60 wt %, and can contain apharmaceutically acceptable carrier in 0 to 99.0 wt %, preferably in 40to 99.0 wt %, of the whole pharmaceutical composition.

When the compound of the present invention is used as a prophylactic ortherapeutic agent for the above-described disease or illness, a dosageand a frequency of administration depend on a patient's sex, age,weight, a degree of symptoms, a type and a scope of a therapeutic effectto be aimed at, and the like. However, in general, for oraladministration, 0.001 to 10 mg thereof is administered, preferably 0.01to 2 mg is administered one to several times, to an adult per day andper kg of his/her weight. In addition, the compound of the presentinvention can be also prophylactically administered for some symptoms.

OCT3 Detection Agent Including Compound of Present Invention

An OCT3 detection agent including the compound of the present inventionis for detecting whether OCT3 protein is included in biological tissues,cultured cells, artificial membranes, or the like in which an existingamount of the OCT3 protein is desired to be checked, or for obtaining anindex of a content of the OCT3 protein. An aqueous solution of thedetection agent including the compound of the present invention is addeddropwise to biological tissues, cultured cells, artificial membranes, orthe like in which an existing amount of the OCT3 protein is desired tobe checked. Then, the compound of the present invention is bonded to theOCT3 protein, and therefore, a concentration of the compound of thepresent invention in the aqueous solution is reduced. That is, when theconcentration of the compound of the present invention is measured, ifthe concentration of the compound of the present invention is reduced,it can be recognized that the OCT3 protein is present. An antibodyagainst the OCT3 protein is commercially available, and can be used as adetection agent. However, the antibody is high molecular protein, andtherefore, is sensitive to heat. Therefore, it is necessary to store theantibody at low temperature. In addition, the antibody is high molecularprotein, and therefore, it is difficult to store the antibody for a longtime, and manufacturing cost thereof is high. On the other hand, thecompound of the present invention or the like is resistant to heat, canbe stored for a long time at normal temperature, and can be relativelyinexpensively manufactured by chemical synthesis.

Example 1

In order to measure an activity to inhibit substrate uptake by the OCT3in each compound, a histamine uptake experiment was performed asfollows.

A histamine uptake experiment was performed according to a methoddescribed in Br J Pharmacol. 2002; 136 (6): 829-836. In this experiment,HEK293 cells, which are human embryonic kidney cell lines expressing ahuman organic cation transporter 3 (hOCT3), were used. The HEK293 cellswere seeded at 1.5×10⁵ cells/well in a 24-well plate and culturedovernight in a carbon dioxide incubator. After being dissolved in a 100%DMSO solution, the test substance was dissolved in a HBSS-HEPES solution(a buffer solution adjusted to pH 7.4 with 1M sodium hydroxide, bydissolving 9.7 g of Hanks balanced salt, 25 mL of 1.4% sodiumbicarbonate, and 25 mL of 1M HEPES in 940 mL of ultrapure water). Aftera cell culture medium was removed, a pretreatment for 5 minutes wasperformed with 1 mL of the HBSS-HEPES solution. Thereafter, the testsubstance and [3H]histamine (final concentration: 100 nM) were added tothe cells and allowed to react for 1 minute at room temperature. Aftercompletion of the reaction, the reaction was stopped with the ice-cooledHBSS-HEPES solution, and extracellular fluid was aspirated by anaspirator. The cells were then washed two times with the HBSS-HEPESsolution. After washing, the cells were lysed in a 0.5 M sodiumhydroxide aqueous solution. An amount of histamine present in the cellswas determined by measuring a radioactivity in the cell lysate with aliquid scintillation counter. A protein content of the cells wasmeasured using the cell lysate by a Lowry method (J Biol Chem. 1951; 193(1): 265-75). A Histamine uptake amount per protein content when thereis no uptake inhibitor is regarded as 100% of a histamine uptake ratio(control), and the histamine uptake ratio (%) in the presence of 30 μMof the test substance was calculated. In addition, a value calculated bysubtracting this histamine uptake ratio from 100(%) was regarded as anOCT3 inhibition ratio (%). Furthermore, an OCT3 inhibitory activity(IC₅₀ value) was calculated from suppression curves at theconcentrations of 10⁻⁷ to 10⁻³ M of the test substance.

Calculation of Predicted Value of log P

Log P of each compound was calculated by inputting a structure of thecompound to Marvin software (version 5.7.0), and was denoted in Tables.When the OCT3 inhibitor is used as a therapeutic agent for depression,intracerebral transferability becomes a problem. Many existing OCT3inhibitors have a small log P value and bad intracerebraltransferability. A compound having a large log P value was designed, andthe log P value was shown together with the IC₅₀ value. Note that it ispossible to predict the intracerebral transferability using this log Pvalue.

A ratio of a brain concentration with respect to a blood concentration(hereinafter, expressed by Brain/Blood) was predicted from the structureof the compound, and also shown. A plurality of prediction methods hasbeen reported. Brain/Blood was calculated based on Prabha et al., InSilico Modeling for Blood-Brain Barrier Permeability Predictions, Drugabsorption studies, 2008, volume VII, 3, 510-556, using the followingequation.log(Brain/Blood)=−0.0148×PSA+0.152×log P+0.139

Note that PSA represents a polarity surface area, which was calculatedusing the above-described Marvin software.

The Brain/Blood value predicted with the above method was verified withan experiment using BALB/c mice. As test substances in the verificationexperiment, two compounds of SR-4277 and Famotidine were used. A strongOCT3 inhibitory effect of SR-4277 has been confirmed. Both the OCT3inhibitory effect and an antidepressant effect of Famotidine have beenconfirmed. The test substance was administered in 5 mg/kg to the mice.The mice were anesthetized in advance with isoflurane, andexsanguination was performed from the vena cava of the mice five minutesafter the administration. Brains were removed, and weights thereof weremeasured. After that, a brain homogenate was prepared. The collectedblood was subjected to centrifugation, and plasma was thereby prepared.Concentrations of the test substance in plasma and the brain homogenatewere measured with HPLC and MS. Results of the predicted value and themeasured value of Brain/Blood are shown below.

TABLE 1 Predicted Measured Predicted value value value Compound ID logPPSA Brain/Blood SR-4277 3.3 46 0.90 1.10 Famotidine −1.9 176 0.002 0.10

When an experimental error in the verification experiment is taken intoconsideration, in the results of the verification experiment, thepredicted value and the measured value are very close (close in order)to each other. It can be said that the prediction method of theabove-described Brain/Blood value is very excellent in predictionaccuracy. This method was also applied to other compounds, andBrain/Blood values thereof were calculated.

Log P values of the compounds were distributed between −0.2 and 4.6 asshown in the following Table (median 2.7). Therefore, it was predictedthat fat solubility would be high and oral absorption would be good. TheBrain/Blood values of the compounds were distributed between 0.08 and1.72 as shown in the following Table (median 0.64). It was predictedthat the brain concentration of the compound was almost the same as theblood concentration. Therefore, the compounds have not only theexcellent OCT3 inhibitory activity but also excellent utility as an oralagent or a central drug. Many compounds better than famotidine in termsof the OCT3 inhibitory activity and the intracerebral transferabilitywere obtained. It is confirmed that famotidine has the OCT3 inhibitoryactivity (Non-Patent Literature 2) and the antidepressant effect (PatentLiterature 4). Utility in the treatment of depression or the like can beexpected.

A chemical structure of X and the OCT3 inhibitory activity thereof areshown below.

TABLE 2 Series Common structure (expressed in a form of R—X: R is acommon structure) 1

X (expressed in a form of —X: A symbol (*) is given to a Histaminebonding site in a compound uptake in which a bonding portion ratio withOCT3 logP Brain/Blood to a nitrogen atom (N) respect to inhibitionMolecular predicted predicted Series Number Compound ID adjacent to X isnot clear.) control (%) ratio (%) weight value value 1 1 SR- 5410

13.9 86.1 341 3.1 0.61 1 2 SR- 4277

15.4 84.6 343 3.3 0.90 1 3 SR- 5301

16.0 84 325 3.2 0.85 1 4 SR- 5349

17.1 82.9 279 2.8 0.74 1 5 SR- 5351

17.4 82.6 293 3.1 0.84 1 6 SR- 5315

24.3 75.7 371 1.4 0.14 1 7 SR- 5402

25.9 74.1 345 2.6 0.38 1 8 SR- 5406

29.2 70.8 325 2.2 0.33 1 9 SR- 5381

38.3 61.7 323 3.0 0.58 1 10 SR- 5403

40.3 59.7 339 2.6 0.37 1 11 SR- 5405

42.0 58 347 3.6 1.01 1 12 SR- 5355

45.1 54.9 295 2.3 0.46 1 13 SR- 5354

47.0 53 311 2.4 0.14 1 14 SR- 5370

52.2 47.8 245 2.3 0.64 1 15 SR- 5320

55.0 45 307 −0.2 0.08 1 16 SR- 5372

55.0 45 337 2.4 0.35 1 17 SR- 5326

56.9 43.1 348 2.8 0.68 1 18 SR- 5385

58.1 41.9 348 2.5 0.25 1 19 SR- 5333

58.3 41.7 295 2.3 0.46 1 20 SR- 5400

59.2 40.8 331 3.2 0.64 1 21 SR- 5379

60.3 39.7 269 2.9 0.78 1 22 SR- 5309

61.5 38.5 297 3.1 0.84 1 23 SR- 5310

61.8 38.2 283 2.6 0.70 1 24 SR- 5408

64.2 35.8 372 1.1 0.08 1 25 SR- 5308

65.0 35 297 3.1 0.84 1 26 SR- 5380

66.7 33.3 376 2.6 0.35

TABLE 3 Series Common structure (expressed in a form of R—X: R is acommon structure) 2

Histamine uptake ratio with OCT3 logP Brain/Blood X respect toinhibition Molecular predicted predicted Series Number Compound ID(expressed in a form of —X) control (%) ratio (%) weight value value 2 1SR- 5335

55.6 44.4 325 2.6 0.20 2 2 SR- 5414

56.4 43.6 309 2.6 0.69

TABLE 4 Series Common structure (expressed in a form of R—X: R is acommon structure) 3

Histamine uptake ratio with OCT3 logP Brain/Blood X respect toinhibition Molecular predicted predicted Series Number Compound ID(expressed in a form of —X) control (%) ratio (%) weight value value 3 1SR- 5340

41.6 58.4 334 2.5 0.83 3 2 SR- 5371

47.6 52.4 338 2.8 0.92 3 3 SR- 5344

50.6 49.4 446 4.6 1.71 3 4 SR- 5364

71.9 28.1 338 2.8 0.92

TABLE 5 Series Common structure (expressed in a form of R—X: R is acommon structure) 4

X (expressed in a form of —X: A symbol (*) is given to a Histaminebonding site in a compound uptake in which a bonding portion ratio withOCT3 logP Brain/Blood to a nitrogen atom (N) respect to inhibitionMolecular predicted predicted Series Number Compound ID adjacent to X isnot clear.) control (%) ratio (%) weight value value 4 1 SR- 4229

38.7 61.3 366 3.3 0.40

TABLE 6 Series Common structure (expressed in a form of R—X: R is acommon structure) 5

X (expressed in a form of —X: A symbol (*) is given to a Histaminebonding site in a compound uptake in which a bonding portion ratio withOCT3 logP Brain/Blood to a nitrogen atom (N) respect to inhibitionMolecular predicted predicted Series Number Compound ID adjacent to X isnot clear.) control (%) ratio (%) weight value value 5 1 SR- 4281

58.5 41.5 353 4.6 1.09 5 2 SR- 4233

72.6 27.4 397 4.2 0.66

TABLE 7 Series Common structure (expressed in a form of R—X: R is acommon structure) 6

X (expressed in a form of —X: A symbol (*) is given to a Histaminebonding site in a compound uptake in which a bonding portion ratio withOCT3 logP Brain/Blood to a nitrogen atom (N) respect to inhibitionMolecular predicted predicted Series Number Compound ID adjacent to X isnot clear.) control (%) ratio (%) weight value value 6 1 SR- 4234

66.7 33.3 396 2.7 0.63

TABLE 8 Series Common structure (expressed in a form of R—X: R is acommon structure) 7

X (expressed in a form of —X: A symbol (*) is given to a Histaminebonding site in a compound uptake in which a bonding portion ratio withOCT3 logP Brain/Blood to a nitrogen atom (N) respect to inhibitionMolecular predicted predicted Series Number Compound ID adjacent to X isnot clear.) control (%) ratio (%) weight value value 7 1 SR- 4290

47.9 52.1 388 3.1 0.54 7 2 SR- 4214

49.5 50.5 374 2.5 0.44 7 3 SR- 4207

54.8 45.2 353 3.7 1.05 7 4 SR- 4280

59.0 41 341 1.9 0.40

TABLE 9 Series Common structure (expressed in a form of R—X: R is acommon structure) 8

Histamine uptake ratio with OCT3 logP Brain/Blood X respect toinhibition Molecular predicted predicted Series Number Compound ID(expressed in a form of —X) control (%) ratio (%) weight value value 8 1SR- 5327

54.5 45.5 355 2.7 0.73 8 2 SR- 5321

56.7 43.3 391 4.0 1.16

IC₅₀ values of some compounds and an IC₅₀ value of famotidine having thestrong OCT3 inhibitory activity, measured simultaneously as a comparisonare as follows.

TABLE 10 Compound ID OCT3 inhibitory activity, IC₅₀ value (μM) SR-42778.2 SR-4056 12.7 SR-4229 25.3 SR-4241 25.5 SR-4272 27.2 SR-4211 29.6SR-4061 30.8 SR-4059 38.0 SR-4074 48.8 Famotidine 67.6

Particularly, SR-4277 has IC₅₀ of 8.2 μM and IC₈₀ of 30 μM. SR-4277 hasthe strong inhibitory activity. Note that it is easily estimated that acompound having the OCT3 inhibitory activity has OCT1 and OCT2inhibitory activities because the OCT3 is very similar to the OCT1 andthe OCT2 in amino acid sequences.

The imidazopyridine derivative of the present invention is a strong OCT3protein inhibitor, and is useful as an OCT3 detection agent.

When an imidazopyridine derivative aqueous solution is added dropwise tobiological tissues, cultured cells, artificial membranes, or the like inwhich an existing amount of the OCT3 protein is desired to be checked,the imidazopyridine derivative is bonded to the OCT3 protein, andtherefore, a concentration of the imidazopyridine derivative in theaqueous solution is reduced. When this concentration is reduced, it isunderstood that the OCT3 protein is present. As a specific example, amethod for detecting the OCT3 protein can be realized by a histamineuptake experiment described below.

For example, a histamine uptake experiment is performed according to amethod described in Br J Pharmacol. 2002; 136 (6): 829-836. An existingamount of the OCT3 protein can be estimated from an amount of a compoundfree in the extracellular fluid in a method similar to a methoddescribed in Japanese Patent No. 1936624. In the experiment, HEK293cells, which are human embryonic kidney cell lines expressing the humanorganic cation transporter 3 (OCT3) are prepared as a positive control,and cell lines the OCT3 expression of which is desired to be checked areprepared as test cells. The cells are seeded at 1.5×10⁵ cells/well in a24-well plate and cultured overnight in a carbon dioxide incubator.After being dissolved in a 100% DMSO solution, the test substance wasdissolved in a HBSS-HEPES solution (a buffer solution adjusted to pH 7.4with 1M sodium hydroxide, by dissolving 9.7 g of Hanks balanced salt, 25mL of 1.4% sodium bicarbonate, and 25 mL of 1M HEPES in 940 mL ofultrapure water). After a cell culture medium is removed, a pretreatmentfor 5 minutes is performed with 1 mL of the HBSS-HEPES solution.Thereafter, the compound of the present invention as the test substanceand histamine (final concentration: 100 nM) are added to the cells andallowed to react for 1 minute at room temperature. After completion ofthe reaction, the reaction is stopped with the ice-cooled HBSS-HEPESsolution, and extracellular fluid is collected.

By analyzing the collected extracellular fluid with LC/MS, it ispossible to identify a concentration and an existing amount of thecompound of the present invention in the extracellular fluid. In thisway, by subtracting the amount of the compound in the collectedextracellular fluid from the amount of the administered compound, it ispossible to calculate an amount of the compound bonded to the OCT3, andit is possible to confirm presence of the OCT3 protein in the cell.Another method for estimating the concentration of the compound of thepresent invention in the extracellular fluid is as follows. Standardsolutions of the compound of the present invention, having a pluralityof concentrations, are prepared in advance, and absorbance thereof ismeasured in advance. Subsequently, the absorbance of the extracellularfluid collected in the above-described histamine uptake experiment ismeasured and compared with the measured value in the standard solutionmeasured in advance. The concentration can be thereby easily estimatedeven without using the LC/MS.

An antibody against the OCT3 protein is commercially available, and canbe used as a detection agent. However, the antibody is high molecularprotein, and is sensitive to heat (stored at 4° C.). Therefore, it isdifficult to store the antibody for a long time, and manufacturing costthereof is high. On the other hand, the imidazopyridine derivative isresistant to heat, can be stored for a long time at normal temperature,and can be inexpensively manufactured by chemical synthesis.

Example 2

Example 2 relates to a method for evaluating an antidepressant effectand anti-symptoms suggesting depression. Currently, the most generalmethod for evaluating the antidepressant effect is a forced swimmingtest developed by Porsolt et al. (Porsolt R D et al., Arch IntPharmacodyn. 1977; 229: 327-336). In this forced swimming test, mice orrats as test animals are forced to swim in water tanks from which themice or rats cannot escape. Then, an immobility behavior of the testanimals after an escape behavior thereof (a state in which only the headis above the water surface and the test animals are floating withoutmoving the hands or feet) is observed. When the test animals are putinto the water tanks again 24 hours or more later, the immobilitybehavior is expressed earlier than in the first experiment. Duration ofthis immobility behavior for a certain time (usually about 5 minutes) isrelatively accurately reproduced.

It is known that existing antidepressants clinical effectiveness ofwhich has been recognized specifically and significantly suppress theduration of the immobility behavior induced in this forced swimmingtest. It is considered that the existing antidepressants are useful fordetecting the antidepressant effect. Test operation of this method isextremely simple. Therefore, this method is widely used in pre-clinicalevaluation of novel antidepressant candidates and phenotypic analysis ofgenetically modified animals (Minoru Tsuji et al., Japanesepharmacological magazine, v130, p 97-104, 2007).

The following method is usually used as a test design using this method.First, standard antidepressants (for example, tricyclic antidepressants)as a positive control drug, and a buffer solution etc. including no drugas a negative control, are administered respectively to differentindividual animals. The experimental conditions of the forced swimmingtest are set so as to be able to detect “a change in behaviorspecifically occurring”.

Subsequently, a test substance is administered in a similar schedule tothe positive control drug. When it is confirmed that a similar change inthe behavior to the positive control drug occurs, it can be concludedthat the test drug can be expected to have the antidepressant effectwhich is a similar clinical effect to that of the positive control drug(Yutaka Nakagawa, practice behavioral pharmacology, Kinpodo, 2010, p35-42).

Note that consideration is required to be given in order to obtain astable experimental result by constantly setting experimental conditionsused in this test, such as weights of mice, a diameter of a cylindricalwater tank, and a water depth in the water tank, to fixed values. Inaddition, it is known that expression time of the immobility behaviorvaries depending on water temperature in the water tank. Therefore, thewater temperature throughout the test needs to be kept constant (usuallyabout 24° C.). It is effective and popular to set high water temperatureabout 1.0 to 1.5° C. higher than room temperature (Yutaka Nakagawa,practice behavioral pharmacology, Kinpodo, 2010, p 35-42).

Furthermore, it is known that an apparent immobility behavior issuppressed even while a spontaneous movement activity is enhanced byadministration of a central stimulant or the like. Therefore, in orderto confirm the antidepressant effect surely, it is necessary to confirmnot only suppression of the immobility behavior in the forced swimmingtest, but also no change in the spontaneous movement activity of animalsby administration of an antidepressant candidate (Minoru Tsuji et al.,Japanese pharmacological magazine, v130, p 97-104, 2007).

Example 3

Example 3 relates to confirmation of the antidepressant effect by theOCT3 inhibitor and a combined effect thereof with an antidepressantimipramine.

The confirmation of the antidepressant effect by the OCT3 inhibitor andthe combined effect thereof with the antidepressant imipramine can beperformed in a similar manner to a prior literature (Kitaichi. et al.,Neurosci Lett. 2005 Jul. 1-8; 382 (1-2): 195-200). Specifically, a testis performed as follows.

In an experiment, ddY male mice each weighing 28 to 33 g (Japan SLC,Inc.) are used. The ddY mice are non-inbred mice, have high fertility,and grow well. The ddY mouse is a typical strain name for laboratorymice widely used in a variety of tests and research including tests formedicinal, pharmacology, toxicity, and the like. After being acquired,these mice are bred in a room in which temperature (22 to 24° C.),humidity (50 to 60%), and lighting (lighting 8:00 to 20:00) arecontrolled for three or more days. In the first forced swimming test,all the experimental mice are forced to swim in glass cylinders(diameter 15.5 cm, depth 17 cm, water depth 12 cm, water temperature 25°C.) for 300 seconds to measure immobility time. The mice are distributedinto experimental groups (an OCT3 inhibitor-administrated group, apositive control group, and a negative control group) such that anaverage value of the immobility time is almost the same. At this time,mice expressing the immobility time having a difference of 60 seconds ormore from the average value of the immobility time (long or short) areexcluded from the experiment. In order to prevent pheromone or the likeof the mice used in the test from affecting subsequent mice, water inthe water tank is exchanged for each mouse. In the OCT3inhibitor-administrated group, the OCT3 inhibitor which was dissolvedthe day after swimming in a physiological buffer solution (140 mM NaCl,3.0 mM KCl, 1.5 mM NaH2PO4, 1.2 mM MgCl2, 1.2 mM CaCl2, pH 7.4) iscontinuously injected into the third cerebral ventricle with an osmoticpump based on a method of a previous report (J. Chem. Neuroanat. 200020: 375-87). One week after the injection, the mice are forced to swimfor 300 seconds again in the cylinders to measure the immobility time.In the positive control group, the antidepressant imipramine isdissolved in physiological saline (three types of final concentrations4, 8, and 16 mg/kg are prepared). Thereafter, the resultant drug isadministered into the abdominal cavity 30 minutes before the secondforced swimming test starts (a drug having each concentration isadministered to each group as a positive control). In the negativecontrol group, instead of the above-described OCT3 inhibitor, only aphysiological buffer solution is continuously injected into the thirdcerebral ventricle in an administration method and an experimentalschedule similar to those in the OCT3 inhibitor-administrated group toperform the forced swimming test.

In the above-described forced swimming test, a result similar to theresult in the prior literature (Kitaichi. et al., Neurosci Lett. 2005Jul. 1-8; 382 (1-2): 195-200) is estimated. That is, symptoms suggestingdepression are caused in the negative control, and an immobility stateis exhibited in most time of the 300 seconds of the swimming (an averagevalue of the immobility time is about 200 seconds). It is expected thatthis immobility state is significantly reduced in the mice into whichthe OCT3 inhibitor in a sufficient amount with respect to the IC50concentration has been continuously injected (0.25 μl/hr) (an averagevalue of the immobility time is about 70 seconds). When a low dose ofthe antidepressant imipramine (4 mg/kg) or a low dose of the OCT3inhibitor is administered alone (0.25 μl/hr), it is predicted that thereis no difference in the immobility time in the forced swimming test fromthe negative control (an average value of the immobility time is about200 seconds in both cases). However, when both are used together, it canbe expected that the immobility state is significantly reduced withrespect to the negative control (an average value of the immobility timeis about 100 seconds). If the above-described results are obtained, theantidepressant effect of the OCT3 inhibitor is confirmed, and thecombined effect thereof with imipramine can be also confirmed.

Example 4

Confirmation of Change in Spontaneous Movement Activity Before and afterAdministrating OCT3 Inhibitor

In order to eliminate a possibility that “by administrating the OCT3inhibitor, the spontaneous movement activity is enhanced, and theapparent immobility behavior is suppressed (there is no antidepressanteffect)”, the spontaneous movement activity before and afteradministrating the OCT3 inhibitor is measured in a similar manner to theprior literature (Kitaichi. et al., Neurosci Lett. 2005 Jul. 1-8; 382(1-2): 195-200).

In an experiment, ddY male mice are used. The mice which have been bredfor three days or more after the purchase are divided into two groups.The OCT3 inhibitor is continuously injected into the third cerebralventricle in one of the groups with an osmotic pump based on theprevious report (J. Chem. Neuroanat. 2000 20: 375-87). In the othergroup, a sham operation is performed, and a physiological buffersolution is injected into the third cerebral ventricle instead of theOCT3 inhibitor as a negative control. The mice one week after theinjection are placed in a plastic cage (30 cm×35 cm×17 cm), andspontaneous momentum is measured before and after intravenousadministration of a stimulant methamphetamine (1 mg/kg). The spontaneousmomentum is automatically counted with an infrared sensor (MelquestLtd., SCANET SV-10) mounted on the wall. From 120 minutes before theadministration of the stimulant methamphetamine until just before theadministration, the spontaneous momentum in the negative control groupand the spontaneous momentum in the OCT3 inhibitor-administrated groupare measured. From just after the administration of methamphetamineuntil 180 minutes after the administration, stimulant-inducedspontaneous momentum is measured in each group. After the measurement, asignificant difference test is performed for the count number of thespontaneous momentum in each group using a Scheffe method. It isdetermined whether the spontaneous momentum changes statisticallysignificantly (p-value is less than 0.05).

In the above-described spontaneous movement activity test, a resultsimilar to the result in the prior literature (Kitaichi. et al.,Neurosci Lett. 2005 Jul. 1-8; 382 (1-2): 195-200) is estimated. That is,before the administration of the stimulant methamphetamine, the countnumber of the spontaneous movement is almost the same between thenegative control group and the OCT3 inhibitor-administrated group. Afterthe administration of the stimulant methamphetamine, it is predictedthat the count number in the OCT3 inhibitor-not administrated group isalmost twice that in the negative control group and that the countnumber in the OCT3 inhibitor-administrated group is almost 5 times thatin the negative control group. By performing the significant differencetest for the count number, it can be expected that the following can beconfirmed. That is, before the administration of the stimulantmethamphetamine, there is no significant difference between the negativecontrol group and the OCT3 inhibitor-administrated group, and thespontaneous momentum does not change by the administration of the OCT3inhibitor. After the administration of the stimulant methamphetamine, itis expected that the spontaneous movement is statistically significantlyenhanced more than before the administration. Therefore, it can beexpected that confirmation that this test system functions effectivelycan be made. If the above results are obtained, it can be confirmed thatthe OCT3 inhibitor has no spontaneous movement activity. The reducedimmobility time confirmed by the forced swimming test becomes a base forindicating the antidepressant effect.

INDUSTRIAL APPLICABILITY

The present invention can be utilized in a pharmaceutical industry.

The invention claimed is:
 1. A method for the inhibition of an organiccation transporter 3 (OCT3) comprising administrating an OCT3 inhibitorrepresented by the following formula (I), a pharmaceutically acceptablesalt thereof, or a pharmaceutically acceptable solvate thereof, as anactive component, to a subject in order to inhibit the OCT3,

in formula (I) R¹, R², R³, R⁵ and R⁶ can be the same or different, andeach represent a hydrogen atom or a methyl group, R⁴ represents a grouprepresented by formula (II),

in formula (II), X² represents any of the groups represented by thefollowing formulae (1-1) to (1-26), wherein the most left carbon atom inthe following formulae (1-1) to (1-26) represents a carbon atom whichattaches to N in formula (II),


2. A method for the inhibition of an organic cation transporter 3 (OCT3)comprising administrating an OCT3 inhibitor represented by the followingformula (I), a pharmaceutically acceptable salt thereof, or apharmaceutically acceptable solvate thereof, as an active component, toa subject in order to inhibit the OCT3,

in formula (I) R¹, R², R³, R⁵ and R⁶ can be the same or different, andeach represent a hydrogen atom or a methyl group, R⁴ representsfollowing formula (2-1)′ or (2-2)′


3. The method according to claim 1, wherein the subject suffers fromdepression and the OCT3 inhibitor is administered by the subject totreat the depression.
 4. The method according to claim 2, wherein thesubject suffers from depression and the OCT3 inhibitor is administeredby the subject to treat the depression.